Volume 7 Issue 12, December 2008

Dissection of the signalling pathways mediating apoptosis — controlled cell death — in cancer, inflammation and neurodegenerative disorders has stimulated the discovery of a wealth of potential drugs to target this process.

The US FDA can now require companies to develop a risk evaluation and mitigation strategy (REMS) for therapeutic products. Bethan Hughes investigates the recent evolution of risk-management strategies in drug development.

The founder of PureTech Ventures discusses the firm's unique approach to company creation.

The p53 tumour suppressor pathway is an attractive target for the development of anticancer therapies. This Perspective highlights recent progress with agents that modulate components of the p53 pathway — in particular, p53 itself and its negative regulator MDM2 — focusing on how studies of their genetic variations, including mutations in cancer cells and inherited polymorphisms, could help tailor the use of existing agents and aid the development of novel drugs.

The pro-survival BCL-2 family of proteins provides exciting drug targets for the selective induction of apoptosis in cancer cells, in which these proteins are often overexpressed. Lessene and colleagues review the preclinical and clinical data for BCL-2 antagonists, and recommend criteria for establishing the mode of action for this new drug class.

Pro-apoptotic receptor agonists have a remarkable ability to selectively induce apoptosis in a wide spectrum of malignant cells. Ashkenazi discusses the scientific rationale, emerging clinical data and future potential for this exciting new class of anti-cancer drugs.

Endoplasmic reticulum (ER) stress is induced following the accumulation of unfolded proteins in the ER. This triggers the unfolded protein response, which initially acts to compensate for damage, but if prolonged or excessive can trigger cell death. Here, Reed and colleagues discuss the role of ER-initiated cell death pathways in diseases including neurodegeneration, hypoxia, heart disease, diabetes and immune disorders, while identifying promising therapeutic targets.

Apoptosis can be induced by activating/stabilizing p53, and by inhibiting NF-κB. Now, it has been found that a surprising number of small molecules can do both. This article describes the principles behind such dual activity, discusses current candidate molecules and provides an outlook to their future development as anticancer drugs.

Apoptosis, the major form of controlled cell death, has a key role in the pathogenesis of diseases including cancer, inflammation and neurodegenerative disorders. The past decade has witnessed tremendous progress in understanding of the molecular mechanisms of apoptosis regulation, which has revealed a number of highly promising therapeutic targets, particularly for anticancer strategies. This focus provides a cutting-edge overview of the science and business of targeting apoptosis.